(SUVpeak) values across different cohorts
BARCIST 1.0 recommends to report SUVpeak instead of SUVmax to avoid overestimation in the quantification of BAT activity [1], because SUVmax is the single highest uptake pixel in the ROI and could easily be an outlier whereas SUVpeak is the highest average SUV in a 1 cc spherical volume, thereby reducing a potential effect of outliers. This sphere may, or may not, be centered on the highest SUVmax. Letiner et al. [11] found that PET image resolution substantially influences observed BAT SUVmax but whether this resolution also affects SUVpeak in currently unknown. Compared to the BARCIST 1.0 criteria, we found similar SUVpeak values across thresholds in young lean men and overweight/obese men. However, differences were observed between the thresholds that did not use HU vs. all the other thresholds in middle-aged overweight-obese adults. This could be based on the lower amount of 18F-FDG injected with respect to the size/body weight of the participant [ratio between amount of 18F-FDG to BMI (6.8±0.3, 6.5±0.8, and 3.8±0.3 MBq/(kg/m2) in young lean adults, young overweight/obese adults, and middle-aged overweight/obese adults, respectively]. Therefore, the distribution of the tracer among the various tissues may partially explain this finding. In fact, lower doses of 18F-FDG, as used in the cohort of middle-aged overweight/obese adults, may increase noise in the image and, therefore, raise SUVpeak levels [1,8,9]. We found that SUVmax was located in BAT regions irrespective of the threshold used in young lean and young overweight/obese men.
However, in middle-aged overweight/obese men, SUVmax was found
in an unexpected region when no threshold for HU was used. Therefore, omission of HU threshold may have resulted in an artificial SUVmax and consequently SUVpeak, especially in the middle-aged overweight-obese men who received a low dose of 18F-FDG. Similar differences between thresholds and cohort studies were found with SUVmax (data not shown). Therefore, in light of these findings, we support that SUVpeak is the most consistent BAT-related outcome between criteria in the three independently cohorts of adults.
Limitations
We quantified BAT in six different ROIs from cerebellum to thoracic vertebra 4 (Figure 1).
Although most of the BAT detected in humans is localized in the areas covered by the selected ROIs [11], we may have missed BAT depots in axillary, paraspinal or abdominal adipose tissue located in anatomical areas beneath the thoracic vertebra 4 [11]. Our ROIs did not include mouth, nose, or thyroid to avoid false positive results, yet, results persisted when a single ROI from cerebellum to thoracic vertebrae 4 was drawn and when HU criteria were applied (data not shown). In addition, we do not know if these findings can be replicated when the SUV threshold of BARCIST criteria is used in combination with other ranges of HU.
Besides the selection of HU and SUV thresholds, quantification of human BAT volume and activity also depends on other methodological issues such as the cooling protocol, 18F-FDG-PET/CT methodology, segmentation software [17], tracer used (18F-FDG vs. 18F-FTHA [23]), intrinsic factors of the participants such as age, sex, or body composition, or extrinsic factors as outdoor temperature [24] or daily light [25] ,which limit comparisons across studies. To improve the understanding of human BAT measured by 18F-FDG-PET/CT, the reconstruction settings should be harmonized in a similar manner as proposed by the EANM guidelines for 18F-FDG tumor PET imaging[26]. In the present study, the PET/CT scans from young overweight/obese adults did not follow these guidelines, therefore we cannot guarantee that the recovery coefficients of the used
reconstructions are the same. Moreover, methodological differences between cohorts did not allow us to check whether differences between HU and SUV thresholds are of different magnitude. Also the use of different cooling techniques (cooling vests vs.
mattresses) and protocols might have introduced some bias. This study included only healthy male adults. The results should be applicable to other populations, such as women and men with different fat distributions, although this should be verified by replication in other cohorts with larger sample size. Moreover, biopsies of BAT-classical depots would be necessary to identify the density window (in terms of HU) of this tissue in different populations.
CONCLUSIONS
BAT volume and activity as determined by 18F-FDG PET/CT highly depend on the quantification criteria used. Future human BAT studies should conduct sensitivity analysis with different thresholds in order to understand whether results are driven by the selected HU and SUV thresholds. According to our findings, when following an individualized cooling protocol, SUVpeak is
the most consistent marker of maximal BAT activity across study cohorts independent of the HU and SUV threshold used, which may therefore facilitate comparisons across studies. The design of the present study precludes providing any conclusive threshold, but before more definitive thresholds for HU and SUV are available, we support the use of BARCIST 1.0 criteria to facilitate interpretation of BAT characteristics between research groups.
Table 5. Hounsfield Units and standardized uptake value thresholds and software used in BAT human studies from 1st of January 2007 to 10th of March 2017
Studies Hounsfield units Standardized
uptake values Software to quantify BAT
Hadi et al. 2007 [27] NR NR NR
Kim et al. 2008 [28] NR NR NR
Alkhawaldeh et al. 2008 [29] NR NR NR
Basu et al. 2008 [30] NR NR NR
Zukotynski et al. 2009 [31] NR NR NR
Cypess et al. 2009 [2] -250,-50 2.0 PET/CT viewer shareware
Van Marken et al. 2009 [3] NR NR PMOD 2.85
Virtanen et al. 2009 [32] NR NR NR
Saito et al. 2009 [5] NR NR VOX-BASE
Au-Yong et al. 2009 [33] Not used Not used Leonardo workstation
Paidisetty et al. 2009 [34] NR NR NR
Lee et al. 2010 [35] -250,-50 2.0 NR
Skarulis et al. 2010 [36] NR NR MEDx image
Aukema et al. 2010[37] NR NR Osirix DICOM viewer
Pfannenberg et al. 2010 [38] -250,-50 2.0 NR
Park et al. 2010 [39] NR NR NR
Zukotynski et al. 2010 [40] NR NR NR
Garcia et al. 2010 [41] NR NR NR
Rakheja et al. 2011[42] NR NR NR
Ouellet et al. 2011 [43] -100,-10 1.0 MIM software
Pace et al. 2011[44] -250,-50 NR Volumetrix
Orava et al. 2011 [45] NR NR NR
Vijgen et al. 2011 [18] NR NR NR
Lee et al. 2011 [46] NR 2.0 NR
Lee et al. 2011 [47] NR 2.0 NR
Jacene et al. 2011 [48] NR NR NR
Huang et al. 2011 [49] -250,-50 2.0 OsiriX 64-bit software
Yoneshiro et al. 2011 [50] NR NR VOX-BASE workstation
Yilmaz et al. 2011 [51] NR NR NR
Yoneshiro et al. 2012 [52] NR 2.0 VOX-BASE workstation
Vrieze et al. 2012 [53] -250,-50 2.0 Hybrid Viewer; HERMES
Muzik et al. 2012 [54] -250,-50 2.0 NR
Vijgen et al. 2012 [55] NR NR PMOD 2.85
Chalfant et al. 2012 [56] NR NR SliceOmatic image software
Vosselman et al. 2012 [57] -180,-10 1.5 PMOD 3.0
Cypess et al. 2012 [58] -250,-10 2.0 PET/CT Viewer shareware
Ouellet et al. 2012 [59] -100, -10 1.0 NR
Bredella et al. 2012 [60] -250, -50 70%SUVmax PET/CT Viewer shareware
Miao et al. 2012 [61] -250, -50 NR PET/CT Viewer shareware
Vogel et al. 2012 [62] NR NR Osirix DICOM viewer
Schlögl et al. 2013 [63] -250, -10 2.0 SPM8
Ahmadi et al. 2013 [64] -87, -10 NR NR
Banzo et al. 2013 [65] NR NR NR
Carey et al. 2013 [66] -180, -10 1.0 Extended
BrillianceWorkstation
Ruth et al. 2013 [67] -200,-10 2.0 Mathworks, Natick, MA
Lee et al. 2013 [68] NR 2.0 IDL software
Pasanisi et al. 2013 [69] -250, -50 NR Volumetrix
Sugita et al. 2013 [70] NR 2.0 VOX-BASE workstation
Van Rooijen et al. 2013 [71] -150, -50 NR PMOD
Yonsehiro et al. 2013 [72] NR 2.0 VOX-BASE workstation
Yoneshiro et al. 2013 [73] NR 2.0 VOX-BASE workstation
Yoneshiro et al. 2013 [74] NR 2.0 VOX-BASE workstation
Orava et al. 2013 [75] NR NR NR
Muzik et al. 2013 [76] -250,-50 2.0 AMIDE software
Chen et al. 2013 [77] NR 2.0 NR
Vosselman et al. 2013 [78] -180, -10 1.5 PMOD 3.0
Perkins et al. 2013 [79] -250, -50 No limit Syngo MI workplace Bredella et al. 2013 [80] -250, -50 70%SUVmax PET/CT Viewer shareware
van der Lans et al. 2013 [81] -180, -10 1.5 PMOD 3.0
Zhang et al. 2013 [82] -250, -50 2.0 PET/CT viewer software
Admiraal et al. 2013 [83] -250, -50 2.0 Hermes Hybrid Viewer
Admiraal et al. 2013 [84] -250, -50 2.0 Hermes Hybrid Viewer
Persichetti et al. 2013 [85] -250, -50 2.0 MIM software
Vijgen et al. 2013 [86] NR NR PMOD
Boon et al. 2014 [87] Not used 2.0 Hermes Hybrid Viewer
Lee et al. 2014 [88] -300,-10 2.0 NR
Lee et al. 2014 [89] -300, -10 2.0 Software built with IDL
Jang et al. 2014 [90] NR 1.5 syngo.via software
Chondronikola et al. 2014 [91] -100, -10 1.0 NR
Schopman et al. 2014 [92] -250,-50 2.0 Hybrid Viewer; HERMES
Blondin et al. 2014 [93] -150,-30 1.5 NR
Bakker et al. 2014 [12] Not used 2.0 Hermes Hybrid Viewer
Zhang et al. 2014 [94] -250, -50 2.0 NR
Matsushita et al. 2014 [95] Not used 2.0 VOX-BASE workstation
Vosselman et al. 2014 [96] -180, -10 1.5 NR
Zhang et al. 2014 [97] NR NR PET/CT Viewer shareware
Choi et al. 2014 [98] -250,-50 2.0 Extended Brilliance Workspace
Bredella et al. 2014 [99] -250, -50 70%SUVmax PET/CT Viewer shareware
Orava et al. 2014 [100] Not used 1.14 Vinci 2.54.0 software
Cao et al. 2014 [101] NR NR NR
Hanssen et al. 2015 [102] -180, -10 1.5 PMOD 3.0
Hanssen et al. 2015 [103] -180, -10 1.5 PMOD 3.0
Hanssen et al. 2015 [104] -180, -10 1.5 PMOD 3.0
Blondin et al. 2015 [105] -150, -30 1.5 NR
Blondin et al. 2015 [23] -150, -30 1.5 NR
Dinas et al. 2015 [106] Not used Not limit NR
Vosselman et al. 2015 [107] -180, -10 1.5 PMOD 3.0
Cypess et al. 2015 [108] -250,-10 2.0 PET/CT Viewer shareware
Nirengi et al. 2015 [109] -300, -10 2.0 VOX-BASE workstation
Carey et al. 2015 [110] -180,-10 2.0 Extended
BrillianceWorkstation
Wei et al. 2015 [111] -150,-30 2.5 PET/CT viewer shareware
Butler et al. 2015 [112] -250,-50 2.0 NR
Raiko et al. 2015 [113] NR NR NR
Wang et al. 2015 [114] -250,-50 2.0 Volume Viewer software
Puar et al. 2016 [115] -180, -10 1.5 Inveon Research software
Hanssen et al. 2016 [116] -180, -10 1.5 PMOD 3.0
Singhal et al. 2016 [117] -250, -10 1.0 to 30 Fiji Software
Oxguven et al. 2016 [118] -250,-50 2.0 Advantage Windows
Workstation 4.5 Chondronikola et al. 2016 [119] -190, -30 1.5 MIM software
Chondronikola et al. 2016 [120] NR NR NR
Gifford et al. 2016 [121] -200, -1 No limits NR
Yoneshiro et al. 2016 [122] Not used 2.0 NR
Ramage et al. 2016 [123] -150, -30 2.0 PMOD 3.409
Bahler et al. 2016 [124] NR NR NR
Bahler et al. 2016 [125] -250,-50 2.0 Hermes Hybrid Viewer
Salem et al. 2016 [126] -150, -5 2.0 NR
Bahler et al. 2016 [127] -250,-50 2.0 Hermes Hybrid Viewer
Van der Lans et al. 2016 [128] -180, -10 1.5 PMOD 3.0
Gatidis et al. 2016 [129] NR NR NR
Nirengi et al. 2016 [130] NR NR NR
Shao et al. 2016 [131] -100, -10 1.0 TrueD system
Hibi et al. 2016 [132] Not used 2.0 VOX-BASE workstation
Chen et al. 2016 [133] -180, -10 1.5 NR
Lee et al. 2016 [134] -300, -10 2.0 Software built with IDL
Becker et al. 2016 [135] -250, -50 3.0 AW version 4.6, GE
Healthcare
Takx et al. 2016 [136] -250, -50 2.0 TrueD system
Shao et al. 2016 [137] -250, -50 2.0 Syngo True D system
Muzik et al. 2016 [138] -250, -50 2.0 AMIDE software
Blondin et al. 2016 [139] -150, -30 1.5 NR
Blondin et al. 2017 [140] NR NR NR
Gerngrob et al. 2017 [19] -250, -50 2.0 "SYNGO" workstation (Siemens)
Hussein et al. 2017 [141] -190,-30 2.0 NR
Yoneshiro et al. 2017 [142] -300, -10 2.0 NR
NR: Not reported or cited in the study.
Chapter 6
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